Cellular signal transduction is a fundamental mechanism. During the signal transduction, the extracellular stimulation is transmitted intracellularly, to modulate various cellular processes including cell proliferation, differentiation, apoptosis and cell migration. A lot of signal transductions are mediated by growth factors binding to protein tyrosine kinase (PTK) trans-membrane receptor protein tyrosine kinases (RTK).
When RTK is inappropriately or constitutively activated, abnormal RTK activity such as that caused by overexpression or mutations results in uncontrolled cell proliferation or differentiation, and leads to diseases. Known diseases caused by abnormal activity of RTKs include psoriasis, rheumatoid arthritis, many types of cancer, angiogenesis, atherosclerosis and so on. RTK is comprised of many families, and one of them is ErbB family which is comprised of EGFr (also named ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). These RTKs contain an extracellular glycoxylated domain for ligand binding, a transmembrane domain, and an intracellular cytoplasma catalyticaldomain capable of phosphorylating tyrosines of proteins. HER3 does not have an intracellular cytoplasma catalyticaldomain capable of phosphorylating tyrosines of protein. The RTK catalytic activity can be activated either by receptor overexpression or by ligand mediated dimerization. The ErB family RTKs can form homodimers or heterodimers. An example of homodimerization comes from EGFr binding with EGF family ligand (including EGF, transforming growth factor, becellulin epiregulin, etc). The heterodimerization between EGFr family RTKs can be accelerated by heregulin (also named nerregulin) binding. Even though HER3 does not have receptor kinase activity, its heterodimerization with HER2 or HER4 can greatly enhance the receptor kinase dimerization and the tyrosine phosphoryzation catalytic activity. Overactivation of EGFr has been associated with proliferation diseases such as NSCLC, bladder cancer, head and neck cancer, brain cancer and other cancers, while HER2 hyperactivity has been associated with breast cancer, ovarian cancer, uterine cancer, gastric cancer, and pancreatic cancer, etc. Therefore, inhibition of ErbB family RTKs may provide a treatment of the diseases associated with characteristic abnormal erbB family RTK activities. Many publications have discussed the biological activities of erB family RTKs, and their relationship with different diseases, such as the following papers and patents: Reid, A., et al. Eur. J. Cancer, 2007, 43, 481; Doebele, R. C., et al. Lung Cancer, 2010, 69, 1-12; Ocana, A.; Amir, E. Cancer Treat. Rev. 2009, 35, 685-91; Minkovsky, N., et al. Current Opinion in Investigational Drugs 2008, 9, 1336-1346; WO2002/66445, WO1999/09016, U.S. Pat. No. 6,627,634, etc.
Many patents have revealed RTK inhibitors or quinazoline derivatives related technology, for examples: WO9630347 (Chinese patent application CN96102992.7) revealed some 4-anilinylquinazoline derivatives for the treatment of excessive proliferative diseases. WO9738973 (Chinese application CN97194458) and WO2009/140863 (Chinese application CN2009000557) disclosed the preparation and pharmaceutical application of irreversible tyrosine kinase inhibitors. WO0006555 (Chinese application CN99808949) disclosed that certain quinazoline derivatives inhibited RTK activities. WO9935146 (Chinese application CN99803887) disclosed a series of fused heteryl aromatic compounds including quinazolines as active as RTK kinase inhibitors. In addition, Chinese patent applications such as CN01817895, CN93103556, CN98807303, CN96193526, CN01812051, CN99803887, CN0410089867, CN03811739; U.S. Pat. No. 5,521,884, U.S. Pat. No. 6,894,051, U.S. Pat. No. 6,958,335, U.S. Pat. No. 5,457,105, U.S. Pat. No. 5,616,582, U.S. Pat. No. 5,770,599, U.S. Pat. No. 5,747,498, U.S. Pat. No. 6,900,221, U.S. Pat. No. 6,391,874, U.S. Pat. No. 6,713,485, U.S. Pat. No. 6,727,256, U.S. Pat. No. 6,828,320, U.S. Pat. No. 7,157,466 all disclosed that various types of quinazoline derivatives could inhibit the activities of many types of RTKs. Several quinazoline based kinase inhibitors have been approved in US, Europe and many other countries for the treatment of cancer, for example, gefitinib (trade name Irresa), erlotinib (trade name Tarceva), lapatinib (trade name Tykerb), etc. With continued improvement in research of biological mechanism, diagnosis and treatment of cancer treatment of proliferative diseases, especially cancer, is becoming more precise, targeted and personalized. Therefore, there is still an urgent need for clinical applications to develop highly efficacious and highly targeted drugs against proliferative diseases and cancer.